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Arene Ruthenium Catalyst MCAT-53 for the Synthesis of Heterobiaryl Compounds in Water through Aromatic C-H bond Activation Anita Mehta, Biswajit Saha, Ali Koohang, and Mukund Chorghade Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00141 • Publication Date (Web): 14 Aug 2018 Downloaded from http://pubs.acs.org on August 14, 2018
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Organic Process Research & Development
Arene Ruthenium Catalyst MCAT-53 for the Synthesis of Heterobiaryl Compounds in Water through Aromatic C-H bond Activation Anita Mehta*, Biswajit Saha, Ali Aiden Koohang, and Mukund S. Chorghade Chicago Discovery Solutions LLC, 23561 West Main St., Plainfield, Illinois, USA 60544
[email protected] Subst.
[Ru2Cl2(HCOO)3(p-cymene)].Na
DG H
LG
Subst.
+
DG
(MCAT-53) Base Water
Subst.
Subst.
= Directing group = Leaving group = Sustituted
DG LG Subst.
MeO F 3C
MeO H O
N
+
Br
F Me
F
MCAT-53 HCOONa Water
Me
Me N
F 3C
Me
O Intermediate of Anacetrapib
Table of Content
ABSTRACT: A new water friendly MCAT-53 [Ru2Cl2 (HCOO)3(p-cymene)] Na, (sodium η-6-p-cymene dichloro diruthenium triformato complex) has been developed as a catalyst to effect aromatic C-H bond activation and C-C coupling reactions in water. Cross-coupling reactions were performed in DI/distilled water under air and ligand free condition without further activation of the catalyst. Synthesis of an advanced intermediate of CETP inhibitor, Anacetrapib in water has been demonstrated to give a single regioisomer using MCAT-53 catalyst. Keywords: C-H activation, C-C coupling, Ruthenium catalyst, and MCAT-53 INTRODUCTION ently green approaches to synthesize industrially useful biaryls.1f-i This approach is highly desirable, because of readily Functionalized biaryl containing motifs are among the most available starting materials and clean reaction conditions as valuable synthetic scaffolds in organic chemistry due to their corresponding salts of Sn, B, and Zn are not produced, HX is prevalence in natural products, advanced materials and pharthe only side product. maceuticals.1a-d Biphenyl moieties constitute pharmacophores Direct arylation strategies have been formulated for step and in Active Pharmaceutical Ingredients (API) such as losartan, cost economical syntheses of industrially useful biaryls and valsartan, azilsartan.1e polyaryls.1i However, direct C–H bond functionalization reacBiaryl compounds are commonly prepared using well-known tions are limited by the inert nature of most carbon-hydrogen aryl-aryl coupling reactions such as the Suzuki and Stille cou1a,b bonds and the requirement to control site selectivity in moleplings. Typically, conventional coupling reactions involve cules that contain diverse C–H groups.1f-i A practical way to C-C bond formation between an aryl halide and an organomeachieve direct arylation (Scheme 1), also known as proximity tallic agent (Scheme 1), and require stoichiometric amount of induced C-H ortho functionalization, is through transition mettransition metal derivatives. al catalyzed C-H activated C-C coupling with the help of DG’s Scheme 1.Common C-C bond forming reaction strategies (Ortho directing groups). DG's are strong coordinating or cheConventional Direct lating groups that direct transition metal insertion at the ortho Coss-coupling Arylation position, thereby allowing the bond formation between the site catalyst Ar1-X + M-Ar2 Ar1-Ar2 Ar1X + H-Ar2 of metal insertion and a carbon atom on a reaction partner substituted with a suitable leaving group (e.g., halide). The use of M = Deriv. of Sn, B, Zn etc. HX X= Br, Cl ortho directing groups in C-H bond functionalization offers several advantages with respect to substrate scope and applicaWithin our sustainable chemistry programs, we have been intion to total synthesis. Complimentary strategies for directed terested in C-H bond activation and direct arylation as inher-
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C(sp3)-H functionalization include 1,n-hydrogen atom transfer and transition metal catalyzed carbene/nitrene transfer.1f Significant progress has been reported in the last two decades on transition metal catalyzed ortho-directed C-H bond activation and functionalization reactions.1f-i,2 Nitrogen containing substrates such as 2-phenylpyridine, 2-phenyl-2-oxazoline, benzo[h]quinoline, and N-phenyl pyrazole have been exploited to act as ortho-DG groups for aromatic C-H activation in the presence of transition metal complexes for the synthesis of hetero-biaryl compounds.2 This strategy was first developed for palladium catalyzed reactions.2a,b More recently relatively cheaper ruthenium2c-i and rhodium2j,k-m based catalysts have provided good results. There are reports of the utility of simple ruthenium compounds such as RuCl3.H2O and RuCl2(p-cymene) dimer in organic solvents.2n,o Ruthenium alkylidines as precatalysts were used by Ackerman2p (in DMA under anhydrous conditions in an inert atmosphere. A ruthenium (II) carboxylate catalyst, generated in situ from [RuCl2 (p-cymene)]2 and 1-phenyl-1cyclopentanecarboxylic acid (PCCA) in presence of K2CO3, allowed activation of the C–H bond in phenyl-substituted pyrimidines and their direct functionalization with aryl halides in organic solvents.2q Ruthenium catalysts have also proven useful in the synthesis of pharmaceuticals. For example, ruthenium (II) dicarboxylate catalysts were found useful in the synthesis of valsartan.2r Toluene was required as a solvent and the reaction mixture had to be heated to 120 oC. Ackerman2s reported direct arylation of arenes with phenols via ruthenium catalyzed C-H and C-OH functionalization using dry DMA under anhydrous conditions and inert atmosphere. Direct arylation in apolar solvent (i.e. toluene) using Rutheniumcatalyzed C−H bond Activation with carboxylic Acids as cocatalysts was also reported by Ackermann.2t These transition metal complexes catalyzed C-H coupling reactions are performed in N-methyl-2-pyrrolidinone (NMP), N,Ndimethylformamide (DMF), N,N-dimethylacetamide (DMAc), or similar polar organic solvents such as DMA. These solvents are undesirable because of their flammability, cost, toxicity, high boiling points and problems associated with the isolation of the desired products dissolved in these solvents. Decreasing the amount of toxic material is one of the major green chemistry challenges for the pharmaceutical industry.3a Synthetic chemists have traditionally shied away from water and carried out reactions in organic medium for most molecules, and often resort to extreme length to keep all traces of water out of their reaction flasks/reactors.3b Water is considered a cheap and non-toxic alternative to organic solvents. Sharpless3c noted that many reactions such as Claisen rearrangements are dramatically accelerated when performed in aqueous suspension (‘on water’) relative to organic solvents or even neat conditions. Low miscibility of organic compounds with water is not detrimental; in fact it facilitates isolation of product. We were interested in ruthenium complexes as catalysts for performing ligand free catalytic reactions in water. Ruthenium catalysts have already demonstrated tolerance to water in many reactions including olefin metathesis reactions in aqueous medium3d,e. Two approaches have been used to conduct metathesis in water, namely using solubilizing surfactants3f or ultrasound.3g Alternative approach is to modify the catalyst itself.3h,i Ruthenium catalysts have also shown to be useful in CH activated arylations in water as a solvent.2c,2d,2h.
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Phosphine ligands are commonly used for C-H catalyzed reactions to provide chemoselectivity and improved yields.2m Air stable secondary phosphine oxides were also found to be useful in C-H activated C-C coupling reactions.3j Most of the reactions were accomplished under anhydrous conditions and inert atmosphere. There is one example where the catalyst was shown to be stable in aqueous mixed media but the yields of the reaction as determined by gas chromatography were lower in aqueous mixtures (61% in NMP-H2O (1:3) vs 98% in NMP alone). Cyclometallted organoruthenium (II) complex [Ru (COOCH3)2(p-cymene)] was successfully used to effect C-H activation of the aryl group in 2-aryl substituted quinazolines with [RuX2(p-cymene)]2 complexes (X in RuX2(p-cymene]2 being halides)3k. The C-C coupling was carried in organic solvents such as 1,4-dioxane in the presence of 10 mole % triphenyl phosphine as ligand in sealed tube condition. Ligands can be toxic and are often unstable and cost prohibitive. A ligand free C-H activated arylation reactions accomplished under ambient conditions are highly desirable. As stated earlier, DG directed C-C coupling reactions with transition metals are often carried out under the inert atmosphere using either pressure reactors or Schlenk tubes by Dixneuf 4a, Kuzman3k and Ackermann.2n-p For improved ease in handling and manipulation, air stable catalysts that avoid the use of sealed tubes/pressure reactors will be valuable. Ackermann 3j reported examples of C-H arylation under dry and inert gas atmosphere using phosphine oxides as preligands and Ru2Cl2 (p-cymene)2 complex. The catalyst system was promising as unlike previous reactions2l,2s , it was tolerant to the use of reagent grade potassium carbonate as a stoichiometric base that need not be dried. Subsequently, the same group reported insight into the mechanism and identification of a welldefined ruthenium(II) dicarboxylate catalyst, [Ru( (COOMes)2(p-cymene)].4b,c Direct arylation of of C-H bonds was done using ruthenium(II) dicarboxylate catalyst with phenols for the reaction of pyrazole derivatives with 4- methyl phenol in water under nitrogen atmosphere4d. Two protocols for ligand free ruthenium- or palladium-catalyzed direct arylations in user-friendly solvent polyethylene glycol (PEG) were reported by Ackermann.4e This catalyst is air stable and is now commercially available and has been known to promote metaselective C-H activation in dioxane and other organic solvents requiring anhydrous conditions for aklylation reactions with halides as well as the synthesis of angeotensin-II receptor blockers by C-H functionalization with organic halides in organic solvent such as toluene.4f However, a sequential metaortho –C-H functionalization can be achieved with alkyl halides in organic solvents such as dioxane, dichloroethane and toluene under extremely anhydrous conditions.2f Palladium catalyzed C-H activated coupling of aryl iodides with anilides and ureas in the presence of oxidants such as Ag(OAc) in 2 wt% surfactant water solution has been described by Lipshutz.4g,h Surfactants such as Brij 35 or TPGS 750 M in water were considered necessary for the success of the reaction. An oxidant was also required. Ruthenium catalytic complex RuCl2(PPh3)(p-cymene) was successfully used by Dixneuf for arylation of functional arenes with aryl chloride and heteroaryl halides in water without using surfactants.4i Various phosphines were used for [RuCl2(p-cymene)]2/KOAc system for the alkenylation of phenyl oxazolines in ethanol.4j Our investigation has been focused on conducting aryl-aryl coupling reactions in water with aryl halides under ambient
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Organic Process Research & Development
pressure and in air without necessity to use ligands such as phosphines. C-H bond functionalization in water by various ruthenium(II) catalysts and potassium acetate and potassium pivalate was reported by Dixneuf.4a,4k Diethyl carbonate as a more eco-friendly solvent was also used for C-H activated functionalization instead of NMP.4l All reactions were carried out under an inert atmosphere of argon in closed Schlenck tube (pressure
